Circadian Clock Cells: Autonomy, Coupling, and Subtypes

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DESCRIPTION (provided by applicant): Daily oscillations in mammalian physiology and behavior persist even in a constant environment, and their disruption leads to jet lag, sleep disorders, and other maladies. Such "circadian" (ca. 24-hr) rhythms are driven by a biological clock located within the brain, in the suprachiasmatic nucleus (SCN). SCN cells express "clock genes," components of a molecular feedback loop comprising the clock. Most of these, including Per1, oscillate in the SCN. Clock gene expression also oscillates in some peripheral tissues, but damps out after a few days without the SCN. The candidate recently completed M.D./Ph.D. training at Harvard and residency training in psychiatry at the University of Pittsburgh. His Ph.D. thesis work provided key evidence for single cell clocks in the SCN that generate independent circadian oscillations in a culture dish. The objective of this proposal is to enable the further career development of the candidate into an independent scientist with expertise in modern molecular and cellular neurobiology. This will be accomplished through a mentored research project which is a natural extension of the candidate's thesis work, but employs a different range of methodology, including transgenic mice, genetically encoded fluorescent reporters, live cell imaging, and DNA microarrays. Cells dissociated from a Per1-GFP transgenic reporter mouse will be used to determine (1) whether single SCN neurons are truly independent clocks, (2) whether damping of rhythms in peripheral tissues is due to single cell damping or desynchrony, (3) the mechanisms of functional coupling among SCN clock cells, and (4) how functional subtypes of SCN clock cells differ by morphology, immunolabeling, and gene expression profiling. The candidate will have a position in the Department of Psychiatry at UCSD, and initially will work in the research mentor's lab at Scripps Research Institute. This environment will provide an outstanding neuroscience community, a mentor with vast experience and resources related to the methodology proposed, and opportunity for future integration with clinical work in psychiatry.